Current methods of tissue fixation leave much to be desired; essentially relying on technologies developed from the clothing and carpentry industries. Screws, pins, wires, sutures, and buttress plates, are examples of bone and soft tissue fixation implants. These devices have many disadvantages, including the need for subsequent operations for removal and interference with mobility and growth impediments in youths. They also have high rates of complications, such as infection and tissue inflammation.
With the market value of fixation devices estimated at approximately four billion dollars, many attempts have been made to improve upon these implants. Resorbable implants have made inroads in addressing some of the issues above, however they still have problems with the destructive nature of the mechanical fixation. For example, the trauma induced by resorbable suturing on intestinal tissue upregulates enzymes that breakdown collagen (the structural component) for up to 4 days post-procedure—weakening the intestine tissue and raising the probabilities of tears and intestinal leakages—but it's still the standard operating procedure for intestinal anastomoses. Intestinal anastomoses are typically performed for treatment of colorectal cancer.
‘Gluing’ soft-tissues and biomaterials together is far more convenient than sutures and conventional tissue fixation, but development of a suitable bioadhesive has yet to be fully realized. Bioadhesive ‘glues’ are a significant engineering hurdle in numerous fields including wound closures, implantable electronics, meshes for abdominal surgeries, and tissue engineering transplants. Medical grade cyanoacrylates, for example Dermabond® and Super Glue®, and fibrin tissue adhesives, for example Tisseal® and Evicel®, are currently the only commercially available and FDA approved bioadhesives that have addressed soft tissue fixation. Unfortunately, they trade adhesive strength for biocompatibility or vice versa. Cyanoacrylates typically have strong tissue adhesion, but are relatively inflexible. Their brittleness, combined with local tissue toxicity and incapability of local drug delivery limits them to skin and other topical adhesions. Fibrin-based tissue adhesives have many shortcomings as well. Their bioadhesion is ‘hydrogel’ weak, has potential neurotoxicity complications and serious religious concerns due to the predominantly human (or bovine) fibrinogen and thrombin sources. Due to their weak mechanical properties, fibrin tissues adhesives are best suited for control of bleeding.
WO/2010/100410 and WO/2010/100413 disclose functionalized diazo derivatives, including diazopyruvate, and their use for producing a chemically-bound three-dimensional network on or within a substrate, but does not mention any particular application of said diazo compounds for tissue bioadhesion.
WO 2009/097152 relates to calcium-reactive amines and acrylic or methacrylic ester monomers adhesives, and use thereof for adhering dental and medical biomaterials to hard tissues via a molecular bridge formed from to hard tissues such as enamel, dentin, and bone. However, this publication does not mention, nor hint to use of photoactive compounds in bioadhesion, but merely mentions that the claimed formulation can contain light-activated free-radical initiators.
WO 2008/023170 describes a group of diazo compounds used as aryl carbene precursors for use in the process of producing a substrate having an adhesive surface, which allows the substrate to adhere to other materials to be tailored. Said publication however is silent about the use of diazirine derivatives in bioadhesive formulations for tissue fixation.
WO 2004/067044 provides a light-activated adhesive composite suitable for medical and surgical applications. The composite includes a scaffold based on various poly(alpha ester)s such as poly(lactic acid), poly(glycolic acid), poly(L-lactic-co-glycolic acid), poly(epsilon-caprolactone), poly(ethylene glycol), poly(ortho ester)s and poly(anhydrides), and a light-activated adhesive, such as a laser tissue solder incorporating chromophores, for example indocyanine green and methylene blue.
EP 0330344 relates to use of crosslinked collagen as a bioadhesive for sutureless closures of the skin and eye or as a superhydrated material for contact lenses, moist bandage contact lens, lens or corneal implant material, or as a drug delivery agent. According to EP 0330344, collagen, which is an example of amino-acid containing polymers, is crosslinked into a highly molecularly crosslinked product upon photoactivation with photoactive crosslinking reagents, such as diazo or azide derivatives.
Failure of soft tissue bioadhesives to address local tissue fixation and biocompatibility has prompted urgent need for a new bioadhesive that allows biomaterials to be adhered onto soft tissues while maintaining a high level of biocompatibility and adhesive strength.